Imidazoline tranquilizing agents

ABSTRACT

WHERE R is isopropyl, phenyl, or hydroxyethyl and R1 is hydrogen or chlorine. The compounds have utility as tranquilizing agents for warm-blooded animals.   Imidazolines corresponding to the formula

United States Patent 191 Wehrmeister Dec. 10, 1974 IMIDAZOLINE TRANQUILIZING AGENTS [75] Inventor: Herbert L. Wehrmeister, Terre Haute, lnd.

[73] Assignee: Commercial Solvents Corporation,

Terre Haute, Ind.

[22] Filed: Dec. 13, 1973 [21] Appl. No.: 424,591

Related US. Application Data [62] Division of Ser. No. 312,077, Dec. 4, 1972, Pat No.

[52] US. Cl. 424/273 [51] Int. Cl A61k 27/00 [58] Field of Search 424/273 Primary Examiner-Stanley J. Friedman Attorney, Agent, or Firm-Robert H. Dewey; Howard E. Post where R is isopropyl, phenyl, or hydroxyethyl and R is hydrogen or chlorine. The compounds have utility as tranquilizing agents for warm-blooded animals.

3 Claims, No Drawings IMIDAZOLINE TRANQUILIZING AGENTS This is a division of application Ser. No. 312,077, filed Dec. 4, 1972, now U.S. Pat. No. 3,812,111.

BACKGROUND OF THE INVENTION This invention relates to tranquilizing agents for warm-blooded animals. In a particular aspect it relates to certain imidazolines useful as tranquilizing agents.

lmidazolines have long been known in the art. They can be prepared, for example, by the method of Morey, U.S. Pat. No. 2,576,306. lmidazolines have many uses, some of which relate to physiological activity. For example W. Fruhstorfer and H. Muller-Calgan disclosed in U.S. Pat. No. 3,147,275 that certain imidazoline derivatives of alkylated phenol were useful for treating the smooth muscular system to obtain a contraction effect, and also to treat the circulatory system to obtain blood vessel constricting and blood pressure increasing properties.

SUMMARY OF THE INVENTION It is an object of this invention to provide a method for tranquilizing warm blooded animals.

It is another object of this invention to provide tranquilizing agents of the class of imidazolines.

Other objects of this invention will be apparent to those skilled in the art from the disclosure herein.

It is the discovery of this invention that compounds, or pharmaceutically acceptable salts thereof, represented by the formula where R can be isopropyl, phenyl, or hydroxyethyl and R is hydrogen or chlorine are tranquilizing agents for warm-blooded animals.

DETAILED DISCUSSION The imidazolines of the present invention are readily prepared by condensing the appropriate aldehyde with an imidazoline corresponding to the formula in accordance with known methods, e.g. the method of R. F. Purcell, U.S. Pat. No. 3,336,145 who discloses a method for preparing similar ethenyl oxazolines, or by the method of H. L. Wehrmeister, J. Org. Chem. 27, 4418 (1962).

lmidazolines corresponding to the above formula are known in the art. They can be prepared by reacting propionic acid with a diamine corresponding to the formula R1 CH3 it according to the method of Riebsomer, J. Am. Chem. Soc. 70. 1629-32 1948) and J. Org. Chem. 15, 68-73, 237-240, 241-4, 909-17 (1950).

lmidazolines are weakly alkaline materials which form salts with most acids. Many of these salts are water-soluble and are advantageous for administering the compounds. The invention also contemplates, therefore, the administration of pharmaceutically acceptable salts of the compounds herein disclosed as well as the unneutralized compounds.

The compounds of the present invention have been found to exert a depressant action on the central nervous system when tested under standard and accepted pharmacological procedures, in animals, such as mice and rats. They are, therefore, deemed to possess utility in experimental and comparative pharmacology and are of value to treat conditions in animals, such as valuable domestic animals, and in laboratory animals, such as mice, rats and the like, responsive to treatment with central nervous system depressant agents. Specifically, the compounds may be employed to induce a calming effect in animals.

In the pharmacological evaluation of the biological activity of the compounds of this invention, the in vivo effects were tested according to the method of Horn, Biometrics, 12:31 1 (1956). In this test, laboratory mice received the test compound (2 mice per dose level) at one half log-dosage intervals by intravenous injection. The animals were observed by trained observers and pharmacological signs-of tranquilization were noted. The median lethal dose LD and the median effective dose (MED for tranquilization were estimated. The safety factor was taken as the ratio of LD50/MED The invention will be better understood with reference to the following examples. It is understood, however, that the examples are'intended for illustration only and it is not intended that the invention be limited thereby.

EXAMPLE 1 4,4-Dimethyl-1-isopropyl-2-(2-p-chlorophenyl-1- methylethenyl)-2-imidazoline (P-l584), b.p. 143 (0.42 mm)-139 (0.3 mm), was prepared by reacting p-chlorobenzaldehyde with 4,4-dimethyl-1-isopropyl- 2-ethyl-2-imidazoline. The latter compound is made by reacting propionic acid with N-isopropyl-2-methyll ,2-propanediamine.

The LD by oral administration to mice was not determined but was less than 25 mg/kg. The LD was less than 12.5 mg/kg.

The compound was tested for tranquilizing activity by the method of l-Iorn. The LD by intravenous administration was 1.8 (0.56-5.6) mg/kg. The median effective dose for tranquilization was 0.056 mg/kg (0018-018) and the safety factor was 32.0.

EXAMPLE 2 The experiment of Example 1 was repeated in all essential details except that benzaldehyde was substituted for p-chlorobenzaldehyde. The resulting compound 4,- 4-dimethyll -isopropyl-2-( l-methyl-2-phenylethenyl 2-imidazoline (P-1583) had a boiling point of 131-l35 at 2mm. The nuclear magnetic resonance spectrum and infra-red absorption spectrum were consistent with the proposed structure,

The LD by oral administration to mice was not determined, but the LD was less than 12.5 mg/kg.

The compound was tested for tranquilizing activity according to the method of Hour. The LD by intravenous administration was 5.6 mg/kg (1.8-18.0). The

median effective dose for tranquilization was 1.0 mg/kg (032-32) and the safety factor was 5.6.

EXAMPLE 3 The experiment of Example 2 is repeated in all essential details except that 4,4-dimethyl-l-phenyl-2-( lmethyl-Z-phenylethenyl)-2imidazoline is prepared by condensing 4,4-dimethyl- 1 -phenyl-2-ethyl-2- imidazoline with benzaldehyde. The compound exhibits tranquilizing activity by intravenous administration to animals.

EXAMPLE 4 The experiment of Example 2 is repeated in all essential details except 4,4-dimethyl-l-hydroxyethyl-2-(1- methyl-Z-phenylethenyl)Z-imidazoline is prepared by condensing 4,4-dimethyl-l-hydroxyethyl-2-ethyl-2- imidazoline with benzaldehyde. The compound exhibits tranquilizing activity by intravenous administration to animals.

I claim:

1. A method of tranquilizing an animal comprising administrating thereto a tranquilizing amount of a compound corresponding to the formula R CH nHsLM N C (CH3) 2 *z g gg UNITED s'm'iirs FATENT OFFICE CEETEFECATE OF QORR 236F101! Patent No.3, 53,995 Dated December 10, 1974 ln entofl Herbert L. Wehrmeister It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 4, line 3, claim 1, "administrating" should. read administering Columnl, lines 33-6, that portion of the formula reading R C|H CH3CH2-7C should read CH=C \l f Column 1, lines 46-50, the formula should appear as follows:

N F C(CH3)2 CH3CH2 c N-CH Column 1, lines 61-64, the formula should appear as follows:

R NH CH2 C(CH3) 2 I NH2 Signed and Sealed this ninth Day Of September1975 [SEAL] A ttest:

RUTH C. MASON C. MARSHALL DANN AIMSIIIIg Officer (ummissimur ufPaIents and Trademarks 

1. A METHOD OF TRANQUILIZING AN ANIMAL COMPRISING ADMINISTRATING THERETO A TRANQUILIZING AMOUNT OF A COMPOUND CORRE SPONDING TO THE FORMULA
 2. The method of claim 1 wherein R is isopropyl and R1 is chloro and said compound is administered in a dosage within the range of 0.018 to 0.18 mg/kg.
 3. The method of claim 1 wherein R is iSopropyl and R1 is hydrogen and said compound is administered in a dosage within the range of 0.32 to 3.2 mg/kg. 